High-frequency priming stimulation has been shown repeatedly to increase the ability of 1 Hz stimulation to produce long-term depression in hippocampal synapses. Since 1 Hz repetitive transcranial magnetic stimulation (TMS) produces robust depression of the excitability in the motor cortex, we have studied healthy individuals to look at the effect of 6 Hz priming stimulation on this effect. Preliminary data suggest that motor cortex depression from 1 Hz stimulation is longer-lasting when preceded 6 Hz priming. If borne out in more subjects, priming stimulation may make TMS treatments more effective in disorders such as epilepsy and chronic pain. Steroid hormones are known to exert powerful influences on neural function and behavior, but direct physiological evidence has not been found in humans. We have continued our studies of the effects of estrogen and progesterone in the human motor cortex, confirming our earlier findings of excitatory effects of estrogen and inhibition from progesterone. This year we completed a study of women with premenstrual syndrome and showed that they have an abnormal response to the rising progesterone levels in the luteal phase of the menstrual cycle. Where control women showed decreasing excitability in the luteal phase, the women with PMS showed an increase. This finding is compatible with either a defect in the GABA-A receptor system or altered metabolism of progesterone in the central nervous system. While it is known that patients with Parkinson disease and other movement disorders have an altered response to paired TMS of the motor cortex, it is not known whether this measure correlates with disease severity or whether the pattern of findings is specific to the disorder. This uncertainty is due largely to the lack of large and well-controlled studies. In order to answer this question, we initiated two large studies, one in Parkinson disease and one in tic disorder with age-matched healthy controls. These conditions were chosen because the differ widely in their physiology and clinical phenotype. We took measures of clinical severety and administered multiple psychological and cognitive tests in order to look for individual characteristics, independent of disease, that might interact with the physiological dependent variables. In a preliminary analysis, the patterns of physiological response differ significantly among the disease and control groups.